The applicant's laboratory has developed a murine model of airway hyperresponsiveness that recapitulates many of the most salient features of asthma. Further understanding of the important immune requirements for airway hyperresponsiveness in this model is likely to provide insights into the diagnosis, prevention and treatment of this disease. The specific aims of this proposal are as follows: 1) To further define the critical cells, cytokines and other effector molecules required for expression of the asthma phenotype in mice. The roles of T cells, their cytokines and other secreted products, including IL-10, IL-2, and nitric oxide, in mediating airway hyperreactivity will be determined. 2) To extend the model to a more relevant system that incorporates antigens from the house dust mite. The house dust mite is perhaps the most common and potent single cause of asthma. Understanding in detail the relevant antigens and host immune response to this organism will provide critical targets for interruption of the pathologic inflammatory cascade leading to asthma. The molecular immune response to the common dust mite, D. pteronyssinus, will be assessed and T cell clones that incorporate the immunodominant TCR repertoires will be produced and used in the determination of critical mite epitopes. The final aims of this proposal are to devise vaccination strategies that redirect the airway immune response, and so attenuate airway inflammation. Dr. David B. Corry is an Assistant Professor at the University of California at San Francisco and has completed 18 months of clinical Pulmonary Medicine training and 33 months of research. Under the auspices of Dr. Richard Locksley, Dr. Corry developed the mouse model described and has authored or coauthored 7 manuscripts, including one relevant to this model. The funding and other support provided by this award will allow Dr. Corry to pursue investigations of the mechanisms of airway hyperreactivity and methods for their attenuation, as described. The proposed work will be performed at the Lung Biology Center, U.C. San Francisco. The Department of Medicine is fully committed to the career development of Dr. Corry. As such, Dr. Corry will have at least 80% protected time for the duration of the award. UCSF and the Lung Biology Center offer an outstanding environment for academic advancement and training. Dr. Corry s sponsor is Dr. Dean Sheppard; his cosponsor is Dr. Richard Locksley. Both are senior faculty members of UCSF and experts in the fields of immunology and asthma, respectively. Also overseeing Dr. Corry are Advisory Committee members Drs. Ben Kaltreider and Homer Boushey, both experts in airway inflammation and senior Pulmonary Staff. These faculty members will oversee Dr. Corry s career development and scientific progress, as outlined in this proposal.